The network structure of higher animals' brains is of high complexity and is the subject of current research in neurobiology. One aspect of this complexity can be seen in the fact that outwardly discernible functionalities such as memory or object formation is only realized by the interlinking of individual nerve cells. The consequence of this for neurobiological analysis is that the activity of a very large number of nerve cells has to be taken into consideration for understanding the brain. For experimental or apparatus-related reasons, therefore, traditional techniques for deriving neural activity encounter their limits. By way of example, it is no longer possible to detect electrical signals of a nerve cell by penetrating into individual cells using glass microelectrodes in the case of large cell assemblages having ten thousand or even millions of neurons, even in in-vitro experiments.
The prior art discloses methods for detecting the electrical potential of a cell or of a cell assemblage by means of sensors non-invasively, that is to say clearly without penetrating into the nerve cell to be examined. Such a concept is described for example in Thomas, C A et al. (1972) “A miniature microelectrode array to monitor the bioelectric activity of cultured cells” Exp. Cell. Res. 74:61–66. In accordance with this concept, a multiplicity of sensors can be operated simultaneously in time in order to record the activity of a neurobiological substance. In this case, a metal contact made of an inert material such as, for example, gold or platinum is used as sensor electrode. In accordance with the prior art, glass is often used as a substrate since it is optically transmissive and therefore enables the experimental arrangement to be monitored by means of a transmitted light microscope. However, the use of glass as a substrate for a sensor array has the disadvantage that the structure dimensions that can be achieved are not small enough, and that a sufficiently high spatial resolution of the activity of nerve cells cannot therefore be achieved.
A sensor arrangement having metallic electrodes is often referred to as a multi-electrode array (MEA).
A multi-electrode array has a known and often constant distance between adjacent sensor electrodes of the array, thus enabling neurobiologists to produce a so-called “map” of neural activity. In this case, it is possible to use biological samples such as brain samples, for example, in which the interlinking of the neurons is not altered by the preparation. In principle, a multi-electrode array has the advantage that the number of recording electrodes can be chosen to be sufficiently high, so that statistical properties of nerve cells can be detected for example in the case of cells that are similar to one another but are not interlinked with one another.
The function of a nerve cell is of interest for practical applications as a biochemical-electrical signal converter. The activity of neural cells is selectively influenced by specific substances, the fact that many of such substances are water-soluble being advantageous. Molecules that influence the activity of a neuron include, in particular, neurotransmitters, which are the subject of many pharmacological investigations. In particular, multi-electrode arrays with nerve cells, in particular from a rat brain, cultivated thereon have become ideal experimental objects for the development of pharmaceuticals. Advantages reside in the good experimental handling and in promising perspectives for long-term studies. The two-dimensional structure of a pharma-sensor comprising nerve cells and a sensor arrangement is essential for such an application.
The detection of toxic substances is another application of a coupled nerve cell/sensor system. Biosensors are distinguished by a high degree of specificity. Nerve cells, for example, are sensitive predominantly to those substances which are relevant to their metabolism. Therefore, an important area of use of biosensors is environmental monitoring, that is to say the detection of environmental parameters, in particular of toxic substances. However, in military and security fields, too, biosensors are capable of use on the basis of the aspect described. Such a concept is described for example in Gross, G W et al. (1995) “The use of neuronal networks on multielectrode arrays as biosensors” Biosensor&Bioelectronics 10:553–567.
However, it must be emphasized that the field of use of biosensors, in particular of the circuit arrangement according to the invention, of the sensor array according to the invention and of the biosensor array according to the invention, is not restricted to applications with nerve cells.
In the fields of use described or in other fields of use, the following requirements have to be made of sensor arrangements: a sufficient number of sensors are to be able to be operated simultaneously in order to make it possible to obtain a snapshot of the potential conditions on the active surface of the sensor arrangement. Furthermore, the distance between sensor elements or the spatial extent of a sensor element is to be chosen to be sufficiently small (typically 10·m to a few 10·m) in order to obtain a sufficiently good spatial resolution. A further important requirement made of such sensors is that the output signals of two arbitrary sensors of a multi-electrode array, given identical input signals, must likewise be identical. This means, in particular, that static differences in the output signals of the sensor elements (offset), which may be based for example on process fluctuations during the manufacture of the sensor elements, are not permitted to occur.
Solution approaches for forming sensors having the desired properties are, on the one hand, sensor arrangements having so-called IGFETs (Insulated Gate Field-effect Transistors) and, on the other hand, the multi-electrode arrays (MEA) already discussed.
In terms of its basic principle, such a FET is constructed similarly to a metal-insulator-semiconductor field-effect transistor (MISFET). It differs from a conventional MISFET by the fact that the conductivity of the channel region of the transistor is not controlled by means of a metal electrode, but rather by means of electrical or electrochemical processes within an electrolyte above the dielectric, it also optionally being possible for the dielectric to take up charges from the electrolyte. In other words, electrically charged particles to be detected (for example ions passing through the ion channels of nerve cells), via the electrolyte, are in contact with a dielectric layer at the surface of the dielectric, as a result of which a purely capacitive coupling is effected between the electrically charged particles to be detected and the channel region of the FET or else between the electrically charged particles to be detected and the gate electrode of the FET arranged below the dielectric layer of the FET. In other words, the dielectric layer acts like the dielectric of a capacitor which is formed between the electrically charged ions and directly the channel region of the FET or between the electrically charged ions of the gate electrode of the FET, in which case, by means of this capacitive coupling (without resistive components) of the charged particles at the surface of the FET sensor, the conductivity of the FET is altered on account of a sensor event, so that the value of the current flow between source and drain terminals of the FET is a measure of the sensor event. A direct ohmic contact, that is to say a direct penetration of the particles at an electrically conductive region of the FET, is not possible. The coupling is thus purely capacitive coupling.
An alternative solution concept for providing sensor arrangements which meet the abovementioned requirements is multi-electrode arrays. (MEAs). Multi-electrode arrays have an electrically conductive surface, usually a metal electrode, in direct operative contact with the electrically charged particles that initiate a sensor event. In order words, in multi-electrode arrays, the electrically charged particles are in direct operative contact with the surface of an electrode, so that the coupling between the particles to be detected and a sensor electrode is at least partly of resistive type. Although, in multi-electrode arrays, the coupling between the particles to be detected and the electrode may also have capacitive components (so-called Helmholtz layers, that is to say layers of particles having alternately positive and negative charges, may form at the surface of an electrode), the resistive components are nonetheless important. In multi-electrode arrays, therefore, the charge state of a node directly below the metal electrode is directly altered by particles to be detected.
In the case of multi-electrode arrays, it is possible, in turn, to distinguish between two concepts: optically and electrical drivable MEAs.
When using optically addressable multi-electrode arrays, metal electrodes of a multi-electrode array are arranged in matrix form. Dimensions of optically addressable multi-electrode arrays known from the prior art typically have 60 rows and 60 columns, the number of sensor elements resulting from the product of the rows with the columns. The electrodes of a column are in each case connected via a photoresistor to a common column line. A position within the sensor array is selected for example by using a laser to put the photoresistor associated with this position into an electrically conductive state by means of a light pulse. However, this concept has the disadvantage that in each case only one sensor array can be selected at one point in time. Furthermore, optical MEAs have the disadvantage that they have expensive and complicated components. Moreover, on account of the use of macroscopic components, such as a laser arrangement, for example, the construction of such sensor arrangements is often high, which counteracts a miniaturization that is striven for. Since optical MEAs in accordance with the prior art are predominantly formed on the basis of a glass substrate, for example the use of active switching or amplifier units, for example of preamplifiers directly below the electrode, is technologically not possible. Moreover, in the case of the glass substrate technology, a sufficiently small dimensioning of the sensor elements and a sufficiently small distance between the sensor elements are not possible, so that both the temporal and the spatial resolution of the sensor elements require improvement.
One example of an electrically addressable MEA known from the prior art is shown in FIG. 1. The electrically addressable MEA 100 shown therein is formed on a glass substrate 101. By means of a boundary wall 102, an active sensor region 103 is formed in the central region of the electrically addressable MEA 100. A multiplicity of sensor arrays 104 are arranged essentially in matrix form in the active sensor region 103, the sensor arrays 104 being set up in such a way that they can detect a sensor event of an object to be examined that is arranged above them, for example of a nerve cell applied thereto. The electrical signals are conducted away via electrical leads 105 to contact areas 106 in the edge region of the electrically addressable MEA 100. The space requirement for the electrical leads 105 is very high. As a result, the maximum number of sensor arrays 104 that can be achieved is greatly restricted. The present technological limit of known MEAs is 64 sensor arrays. In addition to the severely restricted number of maximum sensor arrays 104 that can be achieved, on account of the separate electrical contact-connection of each individual sensor array 104 by means of electrical leads 105, a sufficiently good spatial resolution cannot be achieved. Furthermore, evaluation of the signals provided at the contact areas 106 requires complicated external evaluation electronics (not shown in FIG. 1), which increase the space requirement of the electrically adjustable multi-electrode array 100. Furthermore, a significant disadvantage of the electrically addressable MEAs 100 known from the prior art can be seen in the fact that the requirement that the output signals of two different sensors of an MEA 100, given identical input signals, are likewise identical is often not fulfilled. This is due, inter alia, to fluctuations in the process technology during the formation of the individual sensor arrays 104 and has the consequence that the detection sensitivity and the reliability of the sensor signals obtained require improvement. In other words different sensor arrays 104 of an electrically addressable MEA 100 have fluctuations with regard to the value of one or more physical parameters of the sensor elements 104, for example as a consequence of fluctuating process conditions during the production thereof, with the result that an unambiguous assignment of an electrical output signal to a sensor signal at an associated sensor array 104 is not possible.
Furthermore, Berdondini, L et al. “High-Density MEA for Electrophysiological Activity Imaging of Neuronal Networks” Proc. ICECS 2001, 1239–1242, September 2001, discloses an all-electronic multi-electrode array with electronic position selection, but this array likewise does not meet the aforementioned requirement that, in the case of different sensor arrays, an unambiguous output signal is to be assigned to a defined input signal.
DE 43 20 881 A1 discloses a combination of a heated lambda probe with a jumplike or binary sensor characteristic with a further heated lambda probe for determining the lambda value in a gas mixture, the output signal of one lambda probe serving to calibrate the other lambda probe.